WO2017207719A1 - Composition de cyclophosphamide et son procédé de préparation - Google Patents

Composition de cyclophosphamide et son procédé de préparation Download PDF

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Publication number
WO2017207719A1
WO2017207719A1 PCT/EP2017/063369 EP2017063369W WO2017207719A1 WO 2017207719 A1 WO2017207719 A1 WO 2017207719A1 EP 2017063369 W EP2017063369 W EP 2017063369W WO 2017207719 A1 WO2017207719 A1 WO 2017207719A1
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WO
WIPO (PCT)
Prior art keywords
cyclophosphamide
process according
solvent
suitable solvent
gas
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2017/063369
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English (en)
Inventor
Santhana Krishnan Srinivasan
Ajeet Kumar Singh
Nirav Jayantibhai PATEL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amneal Pharmaceuticals Co GmbH
Original Assignee
Amneal Pharmaceuticals Co GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amneal Pharmaceuticals Co GmbH filed Critical Amneal Pharmaceuticals Co GmbH
Publication of WO2017207719A1 publication Critical patent/WO2017207719A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles

Definitions

  • the present invention provides a stable formulation of cyclophosphamide and process for the preparation of the same.
  • Cyclophosphamide is a widely used synthetic antineoplastic drug chemically related to the nitrogen mustards.
  • the chemical name for cyclophosphamide is 2-[bis(2- chloroethyl)amino]tetrahydro-2H-l,3,2-oxazaphosphorine 2-oxide, and has the followin structural formula:
  • Cyclophosphamide was one example of a group of cyclic phosphoric acid ester amides which were disclosed in US 3,018,302.
  • Cyclophosphamide comprises of monohydrate and anhydrous forms. Further interconversion between the anhydrous and monohydrate forms is well known in the art, however monohydrate form is more stable.
  • US 4,537,883 (Mead Johnson & Co.) describes various lyophilizates of cyclophosphamide. Preparation involves lyophilizing a solution of cyclophosphamide and one or more excipients (mannitol, sodium bicarbonate, lactose, polyvinyl pyrrolidone (PVP), arginine, and tartaric acid.) and then re-hydrating the product such that it contains about 4% moisture. It was found that use of mannitol as the primary excipient provides superior lyophilizate with thermal stability compared to lyophilizates obtained using other excipients.
  • excipients mannitol, sodium bicarbonate, lactose, polyvinyl pyrrolidone (PVP), arginine, and tartaric acid.
  • US 5,066,647 discloses a stable rapidly dissolving lyophilized composition of cyclophosphamide and alanine.
  • US 5,130,305 discloses lyophilized composition containing cyclophosphamide and sodium bicarbonate as an excipient.
  • Lyophilization has several advantages over the previous dry powder premix formulation such as drying without elevated temperatures, and hence avoids adverse thermal effects. Further it is stored in dry state in which there are relatively few stability problems.
  • cyclophosphamide monohydrate is relatively stable compared to anhydrous cyclophosphamide.
  • the bound water or water of crystallization is removed from the cyclophosphamide in the lyophilizer and so there are stability issues associated with this process.
  • the present invention provides a pharmaceutical composition comprising cyclophosphamide and process for the preparation of the same without lyophilisation. Further, process for the powder formulation of cyclophosphamide according to the present invention doesn't require any terminal sterilization or heat to evaporate solvent used during crystallisation. According to present invention process for preparation of pharmaceutical formulation comprising cyclophosphamide comprises preparation of solution of cyclophosphamide, aseptic filtration and solvent evaporation by means of stirring and gas purging.
  • Figure 1 X PD of the cyclophosphamide prepared according to the present invention.
  • Figure 2 Microscopic images of cyclophosphamide prepared according to the present invention.
  • Present invention provides a stable pharmaceutical composition comprising cyclophosphamide compared to cyclophosphamide formulation prepared using terminal sterilisation or lyophilisation.
  • Present invention further provides process for preparation of a stable pharmaceutical composition comprising cyclophosphamide.
  • composition refers to the composition of a cyclophosphamide compound in a form suitable for administration to a mammalian subject, preferably a human.
  • composition of the cyclophosphamide compound comprises addition of pharmaceutically acceptable excipients, diluents, or carriers.
  • the formulation is preferably a powder formulation for parenteral administration after reconstitution.
  • the term “stable composition” refers to any composition having sufficient stability to have utility as a pharmaceutical agent.
  • the formulation has sufficient stability to allow storage at a convenient temperature, preferably between 0° C. and 30° C, for a reasonable period of time, preferably longer than one month, more preferably longer than three months, even more preferably longer than six months, and most preferably longer than one year.
  • composition and “formulation” are interchangeable and have same meaning.
  • Cyclophosphamide refers to 2-[bis(2-chloroethyl)amino]tetrahydro-2H-l,3,2- oxazaphosphorine 2-oxide, pharmaceutically acceptable salts thereof or hydrates thereof. Following is structure of cyclophosphamide monohydrate.
  • Process for the preparation of stable composition comprising cyclophosphamide comprises following steps.
  • Suitable solvent according to present invention refer to solvent having boiling point less than 100°C. Suitable solvent according to present invention further refer to aprotic solvent having water content less than 10%, more preferably solvent having water content less than 5%, most preferably solvent having water content less than 3%.
  • Aprotic solvent according to present invention is selected from but not limited to acetone, Dichloromethane, Tetrahydrofuran, Ethyl acetate, Cyclohexane, or Acetonitrile.
  • Suitable solvent according to present invention further selected from but not limited to Pentane, Cyclopentane, Hexane, Cyclohexane, Benzene, Chloroform, Diethyl ether, Isopropanol (IPA), n-Propanol, Ethanol, Methanol, tertiary butyl alcohol (TBA), methyl tert-butyl ether (MTBE). More preferably suitable solvents according to present invention is Acetone, Dichloromethane, Acetonitrile, Ethyl acetate, Isopropanol, Ethanol, tertiary butyl alcohol, methyl tert-butyl ether or mixture thereof.
  • solution prepared as mentioned above is filtered aseptically through less than 0.22 ⁇ filter, more preferably 0.2 ⁇ filter, most preferably less than 0.2 ⁇ filter.
  • solution comprising cyclophosphamide is collected in the specialized vessel wherein the solvent is removed during the processing.
  • the solvent is removed during the process by stirring and/or purging/blanketing with gas throughout the process at temperature less than 30°C and solvent vapour is removed.
  • the gas used in the present invention is, but not limited to, inert gas such as nitrogen, argon or the like or mixtures thereof.
  • the gas preferably used in the present invention is nitrogen.
  • the gas Preferred temperature for the process is 5-30°C, more preferably 10-20°C and most preferably at less than 15°C.
  • Specialized vessel according to present invention refers to a pre-sterilized closed vessel comprising a stirrer, inlet for gas and outlet for gas and solvent vapour.
  • Specialised vessel further comprises inlet for filtered solution. Furthermore, specialised vessel optionally comprises one outlet to collect cyclophosphamide after solvent removal. Cyclophosphamide obtained using process described herein does not require terminal sterilisation as the obtained cyclophosphamide according to process described in present invention provides sterile cyclophosphamide.
  • specialised vessel is, but not limited to, figure 3.
  • E is closed vessel
  • C is inlet for filtered solution
  • B is inlet for gas
  • D is outlet for gas and solvent vapour
  • A stirrer
  • F is outlet to collect cyclophosphamide after solvent removal from E.
  • cyclophosphamide powder is aseptically collected in suitable container.
  • suitable container according to present invention is pre-sterilized bag or pre-sterilized container.
  • cyclophosphamide powder is filled in pharmaceutical container in which pharmaceutical formulation is supplied by maintaining aseptic condition. More preferably pharmaceutical container of the present invention is vial. Most preferably pharmaceutical container of the present invention is pre-sterilized / depyrogenated vial.
  • to collect cyclophosphamide in suitable container after solvent removal is optional. After solvent removal cyclophosphamide is filled in pharmaceutical container.
  • Specifically present invention provides a process for the preparation of a stable composition comprising cyclophosphamide, the steps comprising:
  • process step b to f is carried out in aseptic condition.
  • step b to f Due to the continuous process and maintenance of aseptic condition throughout step b to f provides stable composition.
  • Impurity B 0.012 0.009 0.0090 0.007 0.01
  • Cyclophosphamide product obtained as per example 1 have a powder X-ray diffraction pattern substantially as depicted in FIG. 1.
  • Powder X-ray Diffraction was performed using Bruker AXS D8 Advance, the powder X-ray diffraction pattern was measured at room temperature using a Cu Ka filled tube (45kV, 40 mA) as the X- ray source with a wide-angle goniometer, a 1° scattering slit DS, in the range of 2.5° to 50°.
  • FIG. 2 Microscopic images of cyclophosphamide product obtained as per example 1 is depicted in FIG. 2. Microscope Analysis was performed on Carl Zeiss microscope. Sample was prepared by dispersing cyclophosphamide in Glycerol. Observation was done at 40X optical zoom.
  • process of the present invention provide more stable formulation as process of the present invention avoids high processing temperature by use of hot air and degradation due to the same.
  • Process of the present invention is more friendly compared to spray drying or lyophilisation.

Landscapes

  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une formulation stable de cyclophosphamide, n'impliquant pas d'étape de lyophilisation. La présente invention concerne en outre un procédé de préparation d'une composition comprenant du cyclophosphamide. Le procédé comprend les étapes de dissolution du cyclophosphamide, de filtration aseptique de solutions stériles, d'élimination du solvant dans des conditions aseptiques par purge ou isolement du gaz inerte pour obtenir de la poudre de cyclophosphamide, cela étant suivi de l'introduction directe du cyclophosphamide dans le contenant pharmaceutique.
PCT/EP2017/063369 2016-06-02 2017-06-01 Composition de cyclophosphamide et son procédé de préparation Ceased WO2017207719A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201621019138 2016-06-02
IN201621019138 2016-06-02

Publications (1)

Publication Number Publication Date
WO2017207719A1 true WO2017207719A1 (fr) 2017-12-07

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Application Number Title Priority Date Filing Date
PCT/EP2017/063369 Ceased WO2017207719A1 (fr) 2016-06-02 2017-06-01 Composition de cyclophosphamide et son procédé de préparation

Country Status (1)

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WO (1) WO2017207719A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12453737B2 (en) 2018-08-03 2025-10-28 Sinotherapeutics Inc. Method for hydrating lyophilized cyclophosphamide composition and product thereof

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3018302A (en) 1956-12-20 1962-01-23 Asta Werke Ag Chem Fab Novel cyclic phosphoric acid ester amides, and the production thereof
US4537883A (en) 1982-11-12 1985-08-27 Mead Johnson & Company Lyophilized cyclophosphamide
US5036060A (en) 1988-07-25 1991-07-30 Fujisawa Usa, Inc. Cyclophosphamide
US5066647A (en) 1989-04-20 1991-11-19 Erbamont, Inc. Cyclophosphamide - alanine lyophilizates
US5130305A (en) 1988-11-14 1992-07-14 Erbamont, Inc. Cyclophosphamide - sodium bicarbonate lyophilizates
US5418223A (en) 1993-05-20 1995-05-23 Erbamont, Inc. Method for lyophilization of cyclophosphamide and product
US20130172271A1 (en) * 2012-01-04 2013-07-04 Cynthia Fragale Pharmaceutical Spray Drying
US20150290226A1 (en) * 2012-10-29 2015-10-15 Leiutis Pharmaceuticals Pvt. Ltd. Novel lyophilized compositions of cyclophosphamide
WO2016046797A1 (fr) * 2014-09-26 2016-03-31 Intas Pharmaceuticals Ltd. Composition pharmaceutique présentant une uniformité de teneur améliorée

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3018302A (en) 1956-12-20 1962-01-23 Asta Werke Ag Chem Fab Novel cyclic phosphoric acid ester amides, and the production thereof
US4537883A (en) 1982-11-12 1985-08-27 Mead Johnson & Company Lyophilized cyclophosphamide
US5036060A (en) 1988-07-25 1991-07-30 Fujisawa Usa, Inc. Cyclophosphamide
US5130305A (en) 1988-11-14 1992-07-14 Erbamont, Inc. Cyclophosphamide - sodium bicarbonate lyophilizates
US5066647A (en) 1989-04-20 1991-11-19 Erbamont, Inc. Cyclophosphamide - alanine lyophilizates
US5418223A (en) 1993-05-20 1995-05-23 Erbamont, Inc. Method for lyophilization of cyclophosphamide and product
US20130172271A1 (en) * 2012-01-04 2013-07-04 Cynthia Fragale Pharmaceutical Spray Drying
US20150290226A1 (en) * 2012-10-29 2015-10-15 Leiutis Pharmaceuticals Pvt. Ltd. Novel lyophilized compositions of cyclophosphamide
WO2016046797A1 (fr) * 2014-09-26 2016-03-31 Intas Pharmaceuticals Ltd. Composition pharmaceutique présentant une uniformité de teneur améliorée

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
M E CBG: "Cyclofosfamide Sandoz 500 mg, 1000 mg and 2000 mg, powder for solution for injection/infusion, (cyclophosphamide) )Public assessment report", 29 December 2014 (2014-12-29), XP055394536, Retrieved from the Internet <URL:https://mri.cts-mrp.eu/Human/Downloads/NL_H_2977_002_PAR.pdf> [retrieved on 20170728] *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12453737B2 (en) 2018-08-03 2025-10-28 Sinotherapeutics Inc. Method for hydrating lyophilized cyclophosphamide composition and product thereof

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